KELLIE NEWSOME: Which antidepressants and mood stabilizers are best for women, and why you need to keep a tight grip on those Ambien doses. Join us as we highlight the minor and major differences between women and men.

CHRIS AIKEN: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. 

KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue. In 1917, Sigmund Freud set out to solve the battle of the sexes. The idea he settled on, in his essay The Taboo of Virginity, has outlasted most of his other theories: the narcissism of minor differences. The more two people have in common, the more they fixate on small distinctions to feel superior, unique, and preserve their individuality. You see it in neighboring nations, in political factions, and for Freud, it explained so many marriages start on common ground and end in polar conflict.

CHRIS AIKEN: Before we get into the ways medication responses differ between women and men, let's clear the air. First, in the spirit of transparency, Kellie and I got engaged last month. We started dating in 2020, a year after launching the podcast, and we’re going to keep on podcasting after we tie the knot this August. But we also need to clear the air about this narcissism of minor differences. While we emphasize the differences between men and women in this podcast, let’s keep in mind that women and men are more alike than different when it comes to psychiatry, psychology, and neurobiology. When researchers find a difference between male and female brains, it makes headlines — but these are usually chance findings, blips in a sea of similarities. When the findings of the past 30 years are pooled, sex explains only 1% of the variance in people’s brain structure and neural processing. That said, there are a few areas of psychopharmacology where a sex-specific approach pays off. We'll cover 14 of them in this four-part series, starting today with valproate, zolpidem, and antidepressants. We’ll end with a peak at DSM-6. Number 1: When to use and when to avoid valproate in women.

KELLIE NEWSOME: There are two reasons to avoid valproate (Depakote) in women. In pregnancy, it harms the fetus. Outside of pregnancy, it disrupts female hormones. Valproate is the most teratogenic psychiatric medication we have. About 1 in 10 babies exposed to valproate in the womb has a birth defect. The neural tube doesn't close, leaving the spinal cord exposed. Or the skull fuses too early, causing dangerous pressure to build up as the brain grows. It can cause cleft palate, cardiac septal defects, and malformed limbs. Valproate also drops the child's IQ by roughly 10 points.

CHRIS AIKEN: That IQ drop is from in utero exposure. Breastfeeding is a different story. A controlled study of mothers with epilepsy compared those who took valproate and breastfed to those who chose to formula-feed while on valproate. Five years later, the children who breastfed had higher IQs and healthier development. That speaks to the well-established benefits of breastfeeding, and it's a reminder that a drug dangerous to a developing fetus isn't necessarily dangerous to a newborn whose organs have already formed.

KELLIE NEWSOME: The second reason to avoid valproate in women is hormonal. It raises androgens — testosterone and DHEA — leading to acne, male-pattern baldness, weight gain, infertility, and a 2- to 6-fold increase in the odds of polycystic ovarian disease. Women who start valproate before age 20 are most vulnerable.

CHRIS AIKEN: But don't dismiss it entirely. Here are some reasons to prefer valproate in bipolar disorder:

A. Personality type

B. Biomarkers

C. Suicide risk

D. Medication response

Number 2: Keep zolpidem low in women.

CHRIS AIKEN: In 2013, zolpidem (Ambien) became the first psychiatric medication with sex-specific dosing. The FDA cut the maximum dose for women from 10 milligrams to 5 milligrams — or 6.25 milligrams for the controlled-release formulation. The reason is slower clearance. Women metabolize zolpidem about 35% more slowly than men. Body mass accounts for some of that, about a third of the slowing , but the bigger driver is testosterone. In men, testosterone accelerates the enzymes that break down alcohol and zolpidem, which is why women metabolize both of this drugs more slowly.

KELLIE NEWSOME: The FDA's guidance here is firm, and for good reason. Zolpidem only helps people fall asleep 10 to 20 minutes faster than placebo. It does nothing for sleep quality or mental health. At higher doses, it increases falls, complex sleep behaviors — things like cooking or driving in the middle of the night, and morning driving impairment. Put all that together, and it’s hard to argue that the minimal benefits outweigh the risk, especially after a patient injures themselves in an amnestic state, which is the only time we’d be called on to argue the point. Gender affects other z-hypnotics a little, but not enough to change the dosing for all women. Zaleplon and eszopiclone are cleared a little more slowly in women because of smaller body mass, but there's no enzyme difference as with zolpidem. Number 3: How SSRIs and MAOIs make a minor difference in women with depression.

CHRIS AIKEN: Women respond better to MAOIs and SSRIs than to tricyclics in depression. One reason is that atypical depression is more common in women, the type with oversleeping, overeating, rejection sensitivity, and that heavy feeling in the limbs called leaden paralysis. Atypical depression responds better to those serotonergic agents, whether in women or men, and atypical depression is more common in women. But that doesn’t fully explain the gender effects with SSRIs and MAOIs. Estrogen also plays a role: it influences serotonergic transmission, and both MAOIs and SSRIs depend on that monoamine for their effects.

KELLIE NEWSOME: The difference in responsiveness is real but modest, so let’s stay grounded and not get all narcissistic about it. On the SSRI citalopram, women were 13% more likely to respond and 30% more likely to remit than men in the STAR-D trial. We see a similar female-bias with MAOIs. For tricyclics, women are less likely to respond than men, while bupropion and SNRIs don’t show a clear sex difference. After menopause, all these sex differences in antidepressant response disappear, either because atypical depression is less common after menopause or estrogen’s influence is dampened.

CHRIS AIKEN: Estrogen's interaction with serotonin also explains why some women have premenstrual dysphoria. Serotonin receptors become more sensitive when estrogen falls in the week or two before menses. Some women on an SSRI feel the medication stop working during that window, and a common strategry is is to double the SSRI dose during those two weeks. That same approach underlies the treatment of premenstrual dysphoric disorder, where the SSRI is only used for the luteal phase, the two weeks before menses. Fluoxetine became the first SSRI approved for PMDD in 2000, sold under a new, feminine brand, Sarafem. Sertraline and paroxetine soon followed with approvals of their own, butfluoxetine's long half-life makes it a good starting point if you’re going to stop and start it. We'll cover premenstrual changes more next week.

KELLIE NEWSOME: A quick recap: Avoid valproate in women of childbearing age. It has androgenizing effects and is the only psychiatric medication absolutely contraindicated in pregnancy. Don’t go above 5 mg or 6.25 mg with zolpidem in women. Tell your patient it's a controlled substance and you're bound by the approved dosing. And if antidepressants aren't working in a woman with depression, especially with atypical symptoms, try an SSRI or MAOI. Today’s study is an editorial by Niall Boyce in the Lancet that gives a preview of DSM-6, the first major revision since 2013. The APA has already formed the Strategic Committee. At the helm is committee chair Maria Oquendo, who chairs the department of psychiatry at the University of Pennsylvania and is known for her research on suicide, mood and anxiety disorders, ketamine, the serotonin system, and cultural psychiatry. Dr. Oquendo is the first woman to chair the DSM, and she is joined by vice chair Jonathan Alpert as vice chair. Dr. Alpert is a professor at Albert Einstein school of medicine and his work covers a broad swath from child to geriatrics, drug interactions to Tai Chi, mood disorders to culture and ethics.

CHRIS AIKEN: First on the table is a name change, from the Diagnostic and Statistical Manual to the Diagnostic and Scientific Manual. Most psychiatric treatments are based on statistical outcomes — rating scales — which has led criticism that we lack a scientific basis in pathophysiology, biomarkers, or even mortality reduction. Whether the name change will lead to substantive reform, well, that is the question.

They're also proposing a four-part diagnostic system, reminiscent of the five axes that were abandoned in DSM-5:

Here's how it might look for one patient:

KELLIE NEWSOME: I like this system. It lights up avenues of treatment that I might have missed if they were buried in the labs or social history. With this patient, I can see right away he’s not likely to respond to medications unless his sleep apnea and social isolation are addressed. And the transdiagnostic axis lets me note the anxiety and cognitive problems without jumping to new diagnoses like generalized anxiety disorder or ADHD, which would only muddy the picture.

CHRIS AIKEN: That’s the idea, the goal is personalized medicine: away from fixed categorical diagnoses, toward individualized profiles that integrate symptom patterns, biomarkers, and environmental factors. It’s like a biopsychosocial model, updated for the times.

KELLIE NEWSOME: The committee also hopes to make DSM-6 a living digital document, updated as new evidence emerges. A worthy goal, but we’ll wait for the fine print. They said the same thing last time. If you want to learn more ways to personalize meds, check out our 2020 textbook Prescribing Psychotropics. We've drawn on its Gender chapter throughout this episode. The book has chapters on how to individualize medications and dosing based on age, ethnicity, genetics, diet, medical disorders, and drug interactions — including which formulation of carbamazepine to use and which form of bupropion to avoid.